This invention relates to novel polypeptides. The compounds are useful as antihypertensive agents.
The proteolytic enzyme renin is known to be active in vivo in cleaving the naturally-occurring plasma glycoprotein angiotensinogen, in the case of human angiotensinogen at the bond between the leucine (10th) and valine (11th) amino acid residues at the N-terminal end of the angiotensinogen. The circulating N-terminal decapeptide known as angiotensin I that is formed by the above cleaving action of renin is subsequently broken down by the body to an octapeptide known as angiotensin II. Angiotensin II is known to be a potent pressor substance, i.e. a substance that is capable of inducing a significant increase in blood pressure and is believed to act by causing the constriction of blood vessels and the release of the sodium-retaining hormone aldosterone from the adrenal gland. Thus, the renin-angiotensinogen system has been implicated as a causative factor in certain forms of hypertension and congestive heart failure.
One means of alleviating the adverse effects of the functioning of the renin-angiotensinogen system is the administration of a substance capable of inhibiting the angiotensinogen-cleaving action of renin. A number of such substances are known including antirenin antibodies, pepstatin and naturally-occurring phospholipid compounds.
European Patent Application Publication Number 0 266 950 of Pfizer Inc. refers to nor-statine and nor-cyclostatine polypeptides which are renin inhibitors.
European Patent Application Publication Number 0 314 239 of Merck & Co., Inc. refers to tripeptide renin inhibitors with N-terminal ureido or sulfamido groups.
European Patent Application Publication Number 0 229 667 of Abbott Laboratories claims:
"A renin inhibiting compound of the formula ##STR2## wherein A is hydrogen, lower alkyl, arylalkyl, OR.sub.10 or SR.sub.10 wherein R.sub.10 is hydrogen, loweralkyl or aminoalkyl, NR.sub.11 R.sub.12 wherein R.sub.11 and R.sub.12 are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or wherein A is ##STR3## wherein B is NH, alkylamino, S, O, CH.sub.2 or CHOH and R.sub.13 is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or an unsubstituted heterocyclic or a monosubstituted heterocyclic wherein the substituent is hydroxy, oxo, amino, alkylamino, dialkylamino or loweralkyl, provided that when the heterocyclic is unsaturated the substituent cannot be oxo;
W is C.dbd.O or CHOH;
U is CH.sub.2 or NR.sub.2, provided that when W is CHOH, U is CH.sub.2 ;
R.sub.1 is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, .alpha.,.alpha.-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided if R.sub.1 is phenoxy, thiophenoxy or anilino, B is CH.sub.2 or CHOH or A is hydrogen; R.sub.2 is hydrogen or loweralkyl; R.sub.3 is loweralkyl, loweralkenyl, (alkoxy)alkoxyalkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R.sub.4 is loweralkyl, cycloalkylmethyl or benzyl; R.sub.5 is vinyl, formyl, hydroxymethyl or hydrogen; R.sub.7 is hydrogen or loweralkyl; R.sub.8 and R.sub.9 are independently selected from OH and NH.sub.2 ; and R.sub.6 is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when R.sub.5 and R.sub.7 are both hydrogen and R.sub.8 and R.sub.9 are OH, the carbon bearing R.sub.5 is of the "R" configuration and the carbon bearing R.sub.6 is of the "S" configuration or pharmaceutically acceptable salts or esters thereof."
It will be seen that the claims of the European application cover certain compounds of the present invention. However, the European application merely encompasses certain compounds of the present invention within a broadly claimed genus and neither exemplifies any of the compounds of the present invention nor teaches one skilled in the art that such compounds should be made or how to make them.